The above data from table 3 in
the Eurosurveillance report,
"Effectiveness of seasonal 2010/11 and pandemic influenza A(H1N1)2009
vaccines in preventing influenza infection in the United Kingdom:
mid-season analysis 2010/11", for samples positive for H1N1
between September 2010 to January 2011, demonstrate a vaccine failure
rate of approximately 50%, regardless of vaccination schedule.

This high failure rate was expected based upon the reports of
widespread infections, as well as the elevated levels of severe and
fatal cases in the UK in this period, primarily in December and
January. A vaccine failure was also anticipated due to sequence
data which indicated that November cases were almost exclusively
due to H1N1 with S186P or S188T, and the presence of S188T in all
December sequences from the UK. This domination is largely
dependent on immunological
escape from the immune response generated in response to infections
during the 2009/2010 season or prior vaccinations.

The results in the UK have been extended to most countries in the
northern hemisphere, which have reported a similar domination of
sub-clades with S186P or S188T. This escape however is poorly
represented in antigenic characterization tests, which lack
reproducibility and sensitivity. Unfortunately, this outdate
procedure is the gold standard for vaccine target selection by the WHO
and CDC. Today the WHO announced that the vaccine target for the
northern hemisphere in the 2011/2012 season will again be
A/California/07/2009. Although the recommendation acknowledged
that some isolates produced low reactivity in some antigenic
characterization tests using ferret anti-sera, the selection of the
2009 target once again demonstrates the failure of this approach.

The track record of this approach in the targeting of H1N1 has been
abysmal, and has been largely driven by the poor data generated in the
antigenic characterization test. For the 2007/2008 season, the
vaccine target of Solomon Island/03/2006 (clade 2A) was selected.
The prior target, New Caledonia/20/1999 had been circulating since 1999
and anti-sera directed against this target (designated clade 1)
produced a low reaction against clade 2. However, by the fall of
2007, there was virtually no Solomon Islands (clade 2A) H1N1
circulating. It had been replaced by Brisbane/59/2007 (clade 2B)
in Europe and North America, or Hong Kong/2562/2007 (clade 2C) in Asia
and western North America. The Brisbane/59 was a concern because
of high frequencies of Tamiflu resistance (H274Y).

However, an insensitive ferret anti-sera was used by the CDC.
Since the anti-sera could not distinguish between the clade 2A, 2B, and
2C, all were said to be Solomon Island-like and a vaccine match.
However, the phylogenetic analysis showed that the three sub-clades
were easily distinguished and had multiple amino acid difference.
Moreover, the dominance of 2B and 2C indirectly indicated there were
antigenic difference which led to the dominance of 2B and 2C at the
expense of 2A. These difference were confirmed in a subsequent
anti-sera generated against Brisbane/59 grown in mammalian cells.
This anti-sera readily distinguished 2A from 2B from 2C and led to the
replacement of Solomon Island/3 with Brisbane/59 for the 2008/2009
season. However, Solomon Island was used in the summer of 2008 in
the southern hemisphere, when Tamiflu resistance increased to 100%.

Moreover, the dominant sub-clade of Brisbane/59 also had receptor
binding domain changes (A193T and additional changes at positions 187
and 189, allowing the virus to escape immunological responses generated
against the virus in the prior season. Consequently, the
Brisbane/59 that emerged not only was Tamiflu resistant with HA A193T
and at least one additional change at positions 187, 189, or 196,
leading to vaccine failures when Brisbane was introduced in the
2008/2009 season. Moreover Tamiflu resistance in H1N1 increased
to 100% worldwide.

The problems linked to an insensitive and unreliable antigen
characterization test continued when pandemic H1N1 emerged in the
spring of 2009. The late appearance led to a delay in the fall
vaccine, and the pandemic emerged early, so it had already peaked when
the vaccine was distributed widely. The drop in activity in
November signaled an immunized target population, raising questions
about the vaccine effectiveness for the following year, since the
target was not changed. Selection of a new target was complicated
by an unreliable test.

Initially there was some agreement between testing done by the CDC and
Mill Hill. Both had found a low reactor in Germany and both
viruses had G158E. This result supported data from two other labs
testing H1n1 under different circumstances. MedImmune had tested
a clone with G158E which grew well in eggs, but was not selected as a
target because anti-sera against wild type produced a dramatically
reduced titer (confirming the G158E produced low reactors).
Similarly H1N1 grown in the presence of neutralizing monoclonal
antibodies generated low reactors which had changes in positions
156-159 including G158E.
However, subsequent isolates from the US which had G158E were not
designated low reactors by the CDC, signaling intra-lab
variation.

These differences were compounded when a Ukraine
isolate A/Lviv/N6/2009 was characterized. Mill Hill designated it
as a low reactor, which was a concern because it had D225G.
However, the CDC published a sequence showing that an isolate from the
same patient had D225G and G158E, yet it was still not called a low
reactor by the CDC. An isolate from this patient became a lab
standard and the WHO regional lab in Australia and the HPA in the UK
published data using the standard and both clearly
showed that it was a low reactor. Thus, the CDC data did not
match its own data on G158E in Germany or the low reactor designation
of the Ukraine
isolate generated by three different labs. Moreover, all US
isolates designated as low reactors by the CDC had a change at position
159, strongly suggesting that the assay lacked sensitivity for
detection of low reactors in the US that did not have a position 159
change.

These discrepancies continued this season. Sub-clades with S188T
and S186P emerged in the UK and across the northern hemisphere,
indicating these changes fuel immunological escape. These
sub-clades became dominant and were tested by the CDC. The
testing of isolates collected from patients outside of the US providing
some data signaling immunological escape associated with S188T.
One isolate from Kenya had a mixed signal at position 158, but was
called a low reactor, supporting a contribution by S188T.
Similarly, an isolate from India did not have a change in the positions
156-159, but had S188T and S186P and was designated a low
reactor. However, a US isolate, A/Kentucky/09/2009 had S188T as
well as G158E and D225G, but was still not designated as a low reactor
by the CDC. Moreover, the CDC has yet to identify a low reactor
in the US this season, even though most isolates have S188T or
S186P. This failure of the antigenic characterization test has
led to a recommendation of A/California/07/2009 for the 2011/2012
season, even
though H1N1 has now become the dominant serotype in the US, influenza
is widespread in most of the states, and the pneumonia
and influenza death rate for week 6 is 8.9, just shy of the five
year high of 9.1 set in week 11 in 2008.